Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs) and for thyroid-stimulating hormone (TSH-R) as model 7TMRs to study their structure and function. During this year, we studied several new aspects of the structure and function of TSH-Rs. 1) An important relatively new observation for TSH-Rs is that they are expressed on cells other than the thyrocyte but the role(s) of TSH-R in these cells is not well understood. One prominent cell that expresses TSH-Rs is the adipocyte. We studied the role of TSH-R on fat accumulation in adipocytes. We found a correlation between fat accumulation and TSH-R levels but could not demonstrate a role for TSH-R in adipogenesis. 2) Graves' ophthalmopathy (GO) is a troublesome component of Graves' disease (GD) that occurs in 25% of GD patients but for which there is no medical therapy. We study GO in cells in primary culture taken from the retro-orbital space of patients with GO at decompression surgery. We use these cells to study GO as there is no animal model of GO. We found a critical interaction between the TSH-R and the receptor for insulin-like growth factor type 1 (IGF-1R) in these cells. We showed that this interaction (cross talk) allowed for a synergistic increase in the production of hyaluronan (hyaluronic acid, HA), which is a major component of the dysregulated extracellular matrix in GO. The levels of HA stimulated by TSH were markedly increased in the presence of IGF-1 and the potency of TSH in this effect was increased by nearly 100-fold. We suggest that TSH-R/IGF-1R cross talk is an important component in the pathogenesis of GO. We are pursuing these observations to develop drug-like molecules to act as probes of this biology and as leads for drug development for a medical therapy of GO.